DESCRIPTION (investigator's abstract): The long-term objective of this research is to characterize the physiological role and relevance in the immunological response of an alternative pathway of antigen processing and presentation, known to be active in immature dendritic cells and possibly in central nervous system microglia. Such alternative pathway relay on abundant cell surface expression of empty class II MHC protein and H2-DM for peptide loading and antigen presentation and on secreted dendritic cells proteases for processing of intact proteins into antigenic peptides. Together, these elements comprised an unusual extracellular presentation pathway in which antigen processing and loading occurred entirely outside the cells. The following proposal is aimed to characterize the trafficking pathway of these empty molecules from their synthesis and folding in the ER to their appearance at the cell surface; to understand the developmental regulation of empty class II MHC molecules on immature dendritic cells and their regulation by the cytokine microenvironment; and finally, to define the immunological role of empty class II MHC protein when engaged with T cell receptors expressed on naive, effector and memory subsets of T cell. The proposed research is part of an interactive research project grant. The companion project will focus on the biochemical aspects of antigen processing and peptide loading as part of the characterization of this novel pathway.